Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap

Youngmin A. Lee (), Luke A. Noon, Kemal M. Akat, Maria D. Ybanez, Ting-Fang Lee, Marie-Luise Berres, Naoto Fujiwara, Nicolas Goossens, Hsin-I Chou, Fatemeh P. Parvin-Nejad, Bilon Khambu, Elisabeth G. M. Kramer, Ronald Gordon, Cathie Pfleger, Doris Germain, Gareth R. John, Kirk N. Campbell, Zhenyu Yue, Xiao-Ming Yin, Ana Maria Cuervo, Mark J. Czaja, M. Isabel Fiel, Yujin Hoshida and Scott L. Friedman
Additional contact information
Youngmin A. Lee: Icahn School of Medicine at Mount Sinai
Luke A. Noon: Icahn School of Medicine at Mount Sinai
Kemal M. Akat: Rockefeller University
Maria D. Ybanez: Icahn School of Medicine at Mount Sinai
Ting-Fang Lee: Icahn School of Medicine at Mount Sinai
Marie-Luise Berres: University Hospital RWTH Aachen
Naoto Fujiwara: Icahn School of Medicine at Mount Sinai
Nicolas Goossens: Icahn School of Medicine at Mount Sinai
Hsin-I Chou: Icahn School of Medicine at Mount Sinai
Fatemeh P. Parvin-Nejad: Icahn School of Medicine at Mount Sinai
Bilon Khambu: Indiana University School of Medicine
Elisabeth G. M. Kramer: Icahn School of Medicine at Mount Sinai
Ronald Gordon: Icahn School of Medicine at Mount Sinai
Cathie Pfleger: Icahn School of Medicine at Mount Sinai
Doris Germain: Icahn School of Medicine at Mount Sinai
Gareth R. John: Icahn School of Medicine at Mount Sinai
Kirk N. Campbell: Icahn School of Medicine at Mount Sinai
Zhenyu Yue: Icahn School of Medicine at Mount Sinai
Xiao-Ming Yin: Indiana University School of Medicine
Ana Maria Cuervo: Albert Einstein College of Medicine
Mark J. Czaja: Emory University School of Medicine
M. Isabel Fiel: Icahn School of Medicine at Mount Sinai
Yujin Hoshida: Icahn School of Medicine at Mount Sinai
Scott L. Friedman: Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.

Date: 2018
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DOI: 10.1038/s41467-018-07338-z

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